Trifluoromethylphenyl thiocarbamic acid phenyl esters

ABSTRACT

IN WHICH EACH OF R1 and R2 independently represents hydrogen, halogen or halogenoalkyl; R3 represents hydrogen, halogen, nitro, cyano, hydroxyl, amino, carbamoyl, sulfamoyl phenoxy or sulfonic acid group, alkyl, alkenyl, halogenoalkyl, aralkyl, alkoxy, alkylthio, alkoxyalkyl, alkylthioalkyl, alkylsulphinyl, alkylsulphonyl, S-alkylsulphonylamino, alkylsulphamoyl, dialkylsulphamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylamino, dialkylamino, acylamino, acyl or carbalkoxy; R4 represents hydrogen, halogen or alkyl; and X and Y each independently represents oxygen or sulfur. These compounds and their salts have anthelmintic properties and can be incorporated into animal feeds.   There are disclosed carbamates and thiocarbamates of the formula

United States Patent [72] Inventors Walter Traber Riehen; Alfred Margot,Basel; Jean-Jacques Gallay, Birsfelden, Basel Land, all of Switzerland[2]] Appl. No. 549,497 [22] Filed May 12, 1966 [45] Patented Sept.28,1971 [73] Assignee Geigy Chemical Corporation Greenburgh, N.Y. [32]Priority May 18, 1965, May 18, 1965,May 18,

1965 [3 3 Switzerland [31 6926/65, 6927/65 and 6928/65 [54]TRIFLUOROMETHYLPHENYL THIOCARBAMIC ACID Pl-lENYL ESTERS 9 Claims, N0Drawings [52] US. Cl 260/455, 260/490, 260/465, 260/471, 424/300 [51]int. Cl C07c 155/08, C07c 125/06, A61k 27/00 [50] Field of Search260/455 H, 471 C; 424/300 [56] References Cited UNITED STATES PATENTS3,334,126 8/1967 Miyazaki et al 260/455 FOREIGN PATENTS 1,397,317 3/1965France 260/471 1,288,262 2/1962 France 260/455 OTHER REFERENCES YuleJournal of Medicinal and Pharmaceutical (hemistry" vol. I (l959)pp.l2ll3l Dyson et al. May sChemis-try of Synthetic Drugs 5th ed, (1959)pp. 1,574-575 Primary Examiner Charles B. Parker Assistant Examiner-D.R. Phillips Attorneys-Karl F. Jorda and Frederick H. Rabin ABSTRACT:There are disclosed carhumates and thiocarbamates of the formula:

in which each of R, and R independently represents hydrogen, halogen orhalogenoalkyl; R represents hydrogen, halogen, nitro, cyano, hydroxyl,amino, carbamoyl, sulfamoyl phenoxy or sulfonic acid group, alkyl,alkenyl, halogcnoalkyl, aralkyl, alkoxy, alkylthio, alkoxyalkyl,alkylthioalkyl, alkylsulphinyl, alkylsulphonyl, S-alkylsulphonylamino,alkylsulphamoyl, dialkylsulphamoyl, alkylcarbamoyl, dialkylcarbamoyl,alkylamino, dialkylamino, acylamino, acyl or carbalkoxy; R representshydrogen, halogen or alkyl; and X and Y each independently representsoxygen or sulfur. These compounds and their salts have anthelminticproperties and can be incorporated into animal feeds.

TRIFLUOROMETHYLPHENYL THIOCARBAMIC ACID PHENYL ESTERS The presentinvention concerns new carbamates and thiocarbamates, processes fortheir preparation, anthelmintic compositions and feed stuffs whichcontain the same as active substances, their use for combattingparasitic helminths and for the prevention of helminthiasis as well asother syndromes caused by the presence of helminths, and concerns also aprocess for the production of such compositions. The compositionsaccording to the invention can be either in the form ofveterinary-medical preparations or of feed additives.

In the present description, the term helminths" refers to nematodes,cestodes and trematodes i.e. to worms which infest the gastrointestinaltract, the liver and other organs.

Among endoparasites which occur in farm or domestic animals, helminthsare those which cause the greatest damage to these animals. Animalsattacked by them show retarded growth or poor increase in weight becauseof the insufficient utilizationof fee'd given to them; moreover,injuries may occur which can result in the death of the animals. It is,therefore, of great importance to develop veterinary agents and feedadditives which are suitable for combatting helminths in all stages oftheir development and for preventing damage caused by them(helminthiasis). Hitherto, many substances have been recommended asanthelminthics, but for various reasons they are not whollysatisfactory, be it that they show only a very specific action oncertain helminths and none on others or that their action is either weakif applied in toxicologically tolerable doses or, if they are applied ineffective doses, undesirable side effects appear to lead to severeorganic injuries.

It has now been found that veterinary-medical agents and feed additiveswhich contain as active ingredients carbamates or thiocarbamates of thegeneral formula l:

wherein each of R and R independently from the other representshydrogen, halogen or a halogenoalkyl radical,

R represents hydrogen, halogen, a nitro, cyano, hydroxyl, amino,carboxyl, carbamoyl, sulfamoyl, phenoxy or sulfonic acid group, analkyl, alkenyl, halogenoalkyl, aralkyl, alkoxy, alkylthio, alkoxyalkyl,alkylthioalkyl, alkylsulfinyl, alkylsulfonyl, S-alkylsulfonylamino,alkylsulfamoyl, dialkylsulfamoyl, alkylcarbamoyl, dialkylcarbamoyl,alkylamino, dialkylamino, acylamino, acyl or carbalkoxy radical,

R, represents hydrogen, halogen or an alkyl radical, and

X and Y each independently represents oxygen or sulfur and/or salts ofthese compounds falling under general formula I which contain in theirmolecule substituents capable of forming salts with inorganic andorganic bases or acids, are very effective against helminths and that,because of their low toxicity in warm blooded animals and good toleranceby the organism, these substances are very well suited for eombattingthe said endoparasites and for controlling the disturbances and symptomscaused by them. When used as ingredients, of feed additives, thesesubstances contribute to a rapid increase in weight, better utilizationof the feed, and an improvement in the general state of health of theanimals. Feed additives containing these compounds have, therefore,special importance for the feeding of farm and domestic animals, inparticular for that of growing animals, e.g. of young pigs, cattle, inparticular larrows, calves or lambs, but also horses, dogs, rodents,furhearing animals, fowls, chicken, pets or caged birds.

Furthermore, these new compounds have fungistatic and bacteriostaticproperties so that they can also be used as external disinfectants aswell as for the proteEtion of organic and inorganic materials.

The radicals R,, R R and R can represent halogen atoms up to the atomicnumber 35 e.g. fluorine, chlorine or bromine. As halogenoalkyl radicals,R R and R are, e.g. monoor polyfluorinated methyl or ethyl radicals,monoor polychlorinated methyl, ethyl or propyl radicals, i.e. preferablyfluoroor chloro-lower alkyl radicals. Radicals WEiEEEZEBT HBIGEfl by Rand R, in general formula I are optionally branched chain radicalshaving one to l2 carbon atoms; alkenyl radicals are those having two tofive carbon atoms. By alkyl radicals which are part of a functionalgroup mentioned above symbolized by R;,, those having one to 12 carbonatoms, preferably one to five carbon atoms, are to be understood. Asaralykl radicals, the benzyl and phencthyl radical can be mentioned andas acyl radicals can be mentioned aliphatic radicals such as the acetyl,propionyl or butyryl radical, and also aromatic radicals such as thebenzoyl or cinnamoyl radicals, lower alkanoyl, benzoyl, loweralkanoylamino or benzoylamino radicals being preferred.

As inorganic or organic bases or acids for the preparation of the saltsof those compounds falling under general formula I, which contain intheir molecule substituents capable of forming salts may be mentionedfor instance alkali or alkaline earth metal hydroxide, piperazine,hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,naphthoic acid, embonic acid or pamoic acid.

The new carbamates and thiocarbamates of the general formula l areproduced according to the invention by reacting an aniline derivative ofthe general formula ll wherein R has the same meaning as in formula I,with a phenyl halogenoformate or phenyl halogenothioformate of thegeneral formula III a (III) wherein R R R X and Y have the same meaningsas in formula l and G represents a halogen atom such as chlorine orbromine.

The phenyl halogenoformate or phenyl halogenothioformate of the generalformula "I serving as starting compounds may also be formed in thereaction mixture from phosgene or thiophosgene and a phenol orthiophcnol of the general formula IV wherein R R R and Y have the samemeanings as in formula l and Z represents hydrogen or an alkali metalatom.

The reaction is preferably performed in the presence of a solvent whichis inert to the reaction partners such as an aromatic hydrocarbon, e.g.benzene, toluene, xylene, and aliphatic or aromatic chlorinatedhydrocarbon, an ester, ketone or amide and it is advantageouslyperformed in the presence of a proton acceptor such as an organic base,e.g. a tertiary amine such as pyridine or trialkylamine, an inorganicbase, e.g. an alkali or alkaline earth metal hydroxide or carbonate. Thereaction temperatures lie in the region of 0 to 60 C.

According to another mode of carrying out the process in practice,instead of an aniline derivative of the general formula ll, anisocyanate or isothiocyanate of the general formula V NCX wherein R, andX have the same meanings as given formula I, is reacted with a compoundof the general formula VI wherein R R R and Y have the meanings givenabove, the

EXAMPLE 2 [7.3 Parts of O-pheny] thiochloroformate are added dropwise toa 20-25 warm solution of 19.6 parts of 3- trifluoromethyl-4chloranilineand 7.9 parts of pyridine in 150 parts by volume of acetone, theaddition being made while stirring,. The reaction mixture is thenstirred for 1 hour at room temperature and then poured into I000. partsof water while stirring. A crystalline precipitate is formed which isfilreactron optlonally being performed in the presence of an ortered offunder suction, washed with water and then dried. gamc solvent which isinert to the reaction partners. After recrystallization fromcyclohexane; the N-( 3- The salts of those compounds falling under thegeneral fortrifluoromethyl-4-chlorophenyl)-O-(phenyl) throcarbamate mulal which have a substituent capable of forming salts are obtained meltsat l122. Yield: 27.5 parts= 83 percent of obtained by reacting saidcompounds with inorganic or orthe theoretical. game bases or acids. 15The following compounds are produced by the methods The new carbamatesand thtocarbamates of the general fordescribed in examples 1 and 2:

TABLE 1 CF; R1 X Y Ra Ra R4 *3 H S O H H H 3 H S 0 CF; 3" H H 3 Cl 4' SO H H H 3 Cl 4 S 0 Cl 4" H 3 Cl 4 S O H Br 4' H 3 C14 S O H CH3 4' H 3Cl 4 S O H Tert. CiHo 4' H 3 Cl 4 S O H Tert. CaHn 4' H 3 C14 S O H CHzO4 H 3 C14 S O H C HaO 4' H 3 Cl 4 S O H CHaCO 4' H 3 Cl 4 S O H N02 4' H3 Cl 4 S O H CODE 4 H 3 Cl 4 S 0 H CONH: 4 H 3 C1 4 S O H COO CzHs 4' H3 Cl 4 S O H OH 4' H 3 Cl 4 S O H NH1 4' H 3 Cl 4 S O H SCHz 4' H 3 C14S 0 C12 SO H 4' Cl 6' 3 Cl 4 S 0 CF; 3' H H 3 Cl 4 S 0 CF: 3 Cl 4 H 3 Cl4 S 0 CF; 3 CF: 5' H 3 Cl 4 S 0 Br 2' Br 4' H 3 Cl 6 S O H H H 3 Cl 6 SO H Cl 4' H 3 Cl 6 S 0 C1 2' Cl 4' H 3 Cl 6 S 0 CF; 3 H H 3 Cl 6 S 0 CF:3' 014' H 3 F 6 S O H H H 3 F 6 S O H Cl 4' H 3 CF; 5 S O H H H 3 CFQ 5S O C] 4' H 3 CFg 5 S 0 C1 2' Cl 4 H 3 01% 5 S 0 OF; 3' H H 3 CF; 5 S 0CF; 3' Cl 4' H 3 CF; 5 S O CFa 3 CF; 5 H 3 H O S H H 3 H O S Cl 2' 11 Cl5' 3 Cl 4 O S C14 H 3 C1 6 O S H Cl 4' H 3 CF; 5 0 s H H H 3 CF: 5 O S HCl 4' H 3 Cl 4 S O COONa 4' H 300 3 C14 S O H COONH; 4' H 210-215 Thenumbers designate the position l the substituents.

mula I produced according to the processes described above, are stablein water and have good solubility in the usual organic solvents.

The following examples serve to illustrate the process according to theinvention. Where not otherwise stated, parts and percentages are givenby weight. The temperatures are given in degrees Centigrade.

The term lower" used in connection with an aliphatic radical in thisspecification and the appended claims indicates that such radical hasfrom one to four carbon atoms.

EXAMPLE l EXAMPLE 3 23.7 Parts of trifluoromethyl4-chlorophenyl-isocyanate in 200 parts by volume of chlorobenzene isadded at room temperature while stirring to a solution of 14.4 parts of4- chlorothiophenol in iOO parts by volume of chlorobenzene and themixture is refluxed for 24 hours while stirring. After evaporating offthe chlorobenzene in vacuo. a crystalline residue remains which isstirred with cyclohexane and undissolved parts are removed byfiltration. On evaporating off the cyclohexane, N-(3-trifluoromethyl-4-chlorophenyl )-S-( 4 chlorophenyl) dithiocarbamateis obtained as colorless crystals which melt at l0ll 03.

EXAMPLE 4 I29 Parts of 3-trifluoromethyl-phenylisocyanate and 9.4 partsof 4-chlorophenol are added to parts by volume of anhydrouschlorobenzene and the mixture is heated under reflux for 24 hours. Afterevaporation of the chlorobenzene, the crude residue left in the vacuo isdissolved in warm cyclohexane and the undissolved parts are removed byfiltration. On evaporating off the cyclohexane, the N-(3-trifluoromethylphenyl)-O-(4'-chlorophenyl)- carbamate is obtained whichmelts at l02-l 04.

The following compounds of the general formula I are obtained when usingthe same procedure as described in the examples 3 and 4.

ygen and their salts as mentioned above are preferred. For example thecompound of the formula TABLE 11 5 NIICOC1 No. on R. x Y n, R; R4 M.P.,0. F

s s 8: 3 {111: 4 0 11 4 11 8 g: is distinguished by good activity onAscarides, Oxyura, 4 3 II 0 0 CF; 3' C14 H 135 i H 3 C14 0 0 Cl H 135137 cestodes such as Hymenolepis nana, and also against ne matospiroids.numbers designat'l the P 0mm substltuellts; Anthelmintic compositionsaccording to the invention may EXAMPLE 5 contain, besides the alreadymentioned active ingredients, for instance also the following compoundsof the general formula N-(3-trifluoromethyl-4-chlorophenyl)-O-(4-aminophenl yl)-thiocarbamate hydrochloride is prepared by dissolving l0g. of the free base (Table I, No. 17) in 50 g. of mcthanolichydrochloric acid containing l0 percent by weight of HCl, NH Y Xdiluting the solution with anhydrous diethyl other until the =i= R3above hydrochloride precipitates and filtering off the R: precipitatedhydrochloride. as active ingredients TABLE III NO. CF: E1 X Y R2 R3 R4 3F 4* O S H H 3 H S 0 C12 H H 3 F 4 S O F 2 C F3 5* II 3 CF; 5 O S B! 3 HBr 5 3 CFa 5 S S F 2 H II 3 Br 4 O S Br 3 Br 4' H 3 C14 S O -CH=CHCH3 4H 3 Cl 4 S O H OH: H

CH=C\ 4 9 3 Cl 4 O O H H 10 3 H S O H 'C zH 4 H 11..- 3 C14 0 O H CHzCl4II 12.- 3 C1 4 S O H H 134."- 3 Cl 4 S O H H 14... 3 H O O H OCH2CH:CHZ4 H 15. 3 C14 S O H CH2OCH34 II 16 3 014 S S H CHzCHzOC2II 4 II 17... 3C14 0 S H CH2SCH:44 II 1s. 3 014 s 0 1r it 19. 3 Cl 4 S 0 11 H COCII=CII/4 3 H O S H S CzHs 4 E5 3 Cl 4 S O H S O-CH; 4 .5 3 C1 4 S O H SO'r-CHa 4 H 3 Cl 4 S O H CN 4 H 3 C14 S O H N(CH:)24 H 3 C14 S O H N(CzH)z3 Ii 3 H S O H -NH S O2CH; 4 II 3 C14 S O H CONHCH:4 Ii 3 C14 0 O HOONHC2H54 II 3 H S O H CON(CH3):4 II 3 H O O H -S OzNHz 4 ll 3 C14 S O H-S O2NHCH14 II 3 H S O H SOzNHC I-In4 ll 3 H s o H *SO2NHC12H25 U 3 C14S O H -SO:N(CH:4)24 H 5 Br 2 S S C F: 3 H II 4 H S 0 Br 2 -Br 4 II 2 H S0 Br 2 Br 4 l1 2 H S O C F3 3 II H s The numbers designate the positionof the substituents The carbamates and thiocarbamates of general formulaI Anthelmintic compositions, including feed additives achave a markedanthelmintic action against the most various cording to the inventionwhich contain as active ingredients types of helminths of the orders ofnematodes, trematodes and the compounds of the general formula I, can beadministered ccstodes in pets and domestic animals such as cattle, pigs,hordirectly to animals in the form of solutions, emulsions, suspenses,sheep, goats, dogs, cats, furry animals and fowls. sions, drenches,powders, tablets or boluses or in the form of Compounds of Formula I inwhich X is sulfur and Y is oxgelatin capsules, or they can be admixed totheir feed The active substances can be administered tohelminth-infested animals or to animals to be protected againsthelminths in the form of therapeutical preparations either as one singledose or repeatedly, the single dosage depending on the type of animal,preferably between 10 and 300 mg. per kg. bodyweight. in some cases,better results are obtained or the total amount required for a cure canbe decreased by protracted administration. The concentration in whichthe active substances in the form of such agents are added, e.g. tofeeds or liquids given to animals are between 0.05 and l percent hyweight.

To prepare the forms of application given above, conventional solidcarriers can be used, for example kaolin, talcum, bentonite, sodiumchloride, calcium phosphate, hydrocarbons, cellulose powder, carbowaxes,gelatins, or liquids such as water, if desired with the addition ofsurface active agents, ionic or nonionic dispersing agent or emulsifyingagents, oils and other solvents which do not injure the animal organism.

These agents can also be added in solid form to the animals feed.Suitable carrier materials in feed concentrates (feed additives) are,among others and in addition to those mentioned above, energy-producingfeed, grain feed, protein concentrates, fish meal, soya-bean meal,cotton seed meal and linseed meal. Such a concentrate, usually having aconcentration of about 25 percent by weight, is then thoroughly mixedwith other conventional feed additives or fillers, such as mineralagents, vitamins, antibiotics, chemotherapeutics, bacteriostatics,fungistatics, coccidiostatics, hormone preparations, substances havingan anabolic action or other substances which promote growth, influencethe quality of the meat of animals to be slaughtered or are useful tothe animal organism in any other way. in this manner, a premixture (feedadditive) is obtained which contains, e.g. 5-l0 percent by weight of theactive substance of the general formula I. A suitable amount of thispremixture is then equally distributed by means of a mixer in a usualcommercial food such as a grain mixture or other vegetable or animalsubstances. The finished feed contains the substances of formula 1preferably in a concentration of about 0.001-1 percent by weight.

Tests performed on hens, mice and rats suffering from helminthiasis aredescribed below. As has been shown in these tests, the active substancesof general formula I are well tolerated by the animal organism.

fifth day. Furthermore, the number of chickens free from worms wasrecorded.

Ascaridia galli eliminated from Daily 5 hens in 4 days dose in No. ofmgJkg. In percent hens tree body- Abs. of total from Active substanceweight No. No. worms N,O-bis-(litrlflnoromethylphenyl) carbamate 500 177100 5 N-(g-trllipizrofitghyl-tchlorop eny 3 r uoromethylphenyl)carbamatc. 33 N-(mlt-trifltltloronliftgiyi --hl e orop eny -c orophenyl)dithiocarbamate. 58g gN-(3-trlfluoromethyl-4-ehlorophenyl)-8-(3',5-dichloro phenyl)dithiocarbamate- 500 68 100 5 N-(3-trlfiu0romethylphenyl) S-(phenyl)thioearbamate- 500 32 100 5 N,O-bis(3-trlfiuoromethylphenyl)thiocarbarnate. 500 168 100 5N-(3,5-ditrifiuoromethylphenyl)-O-(3'-trifiuoromethylphenyl)thiocarbamate 500 154 100 5 N-(3-trifiuoromethylphenyl)- O-(phenyl)thlocarbamate. l 250 28 4 TESTS ON MICE INFESTED WITH HYMENOLEPIS NANAThe active ingredients, in the form of a suspension, were administeredby artificial feeding to white mice which had been artificially infestedwith Hymenolepis nana. Five animals were used for each test. The activeingredients were administered to each group of animals on 3 or 4consecutive days and then the animals were killed and dissected on theeight day after the beginning of the treatment.

The results were evaluated on dissection by counting the number of tapeworms in the intestines of the killed animals, Untreated mice which hadbeen infested in the same way at the same time served as controls.

The agents were tolerated by the mice without any symptoms.

Daily dose in Length Infestation Infestation oi mg./kg. of treatof 5animals control animals bodyment on dissection on dissection Activesubstance weight daysN-(S-trifluoromethylphenyl)-O-(3'-l:rifiuoromethyl4'- chlorophenyl)carbamate- 1,000 3 0 0 0 0 0 6 l4 6 5 13 N-(3-trlfluoromethyl-fi-chlorophenyl)-S- (2',4-dlehlorophenyl)dlthiocarbamate 500 3 0 0 0 0 0 8 2 l2 2 4N-(3.fi-ditrifluoromethylphenyl)-O-(3'-trifluoromethylphenyDdithiocarbarnate100 4 0 0 0 0 0 J 8 ll 14 6N-(3-trifluoromethyl-4-ehlorophenyl)O-(4-eh1orophenyhthiocarbamate 400 30 0 O 0 0 9 8 ll 14 6 TESTS ON HENS INFESTED WITH ASCARlDlA GALLIEVALUATlON The number of Ancaridia galli eliminated by each group oftest animals within 5 days after the first administration of the activesubstance was determined daily and in addition the number of worms stillfound in the intestine after killing on the TESTS ON RATS INFESTED WITHF ASClOLA HEPATICA White laboratory rats are artificially infested withliver flukes (Fasciola hepatica}. On completion of the prepatency time,the infestation of the rats by liver flukes is checked for the presenceof liver fluke eggs in the faces on three different days.

For each test, two infested rats are treated once daily for threeconsecutive days with the active substance which is applied orally inthe form of a suspension. Within the third and fifth week afteradministration of the active substance, the faeces are analyzed once aweek to determine the presence or absence of cggsof liver flukes. At theend of the fifth week the test animals are killed and examined for thepresence of liver flukes.

Daily Control of elimination of dose in eggs 3 times Number of mgJkgliver body- Before After flukes on Activosubstulico weight medicationmedication dissectionN-(3,5-ditrilluorornethylphenyl)-O-(3-trlfluoromethylphenyl) 50Positive"... Negative...

thiocarbamute. N, O-bis-(3-triiluoromethylphenyl) thiocurbamate. 50 do.do 0 N-(3-triiluoromethyl-4-chlorophenyl)-O-(4-ehl0rophenyl) lgg go 00.... 0

thiocarbamate.

The following examples describe the production of anthelmintic agentsaccording to the invention. Parts are given therein as parts by weight.

EXAMPLE I A powder is produced by intimately mixing and milling 50 partsof N-(3-trifluoromethylphenyl)-O-(3'-trifluoromethyl- 4-chlorophenyl)carbamate, 30 parts of Microcell, 19.5 parts of kaolin and 0.5 parts ofethylene oxide-propylene oxide condensate (the product sold under thecommercial name Pluronics F 68). On stirring this pulverulent mixturewith water, a pulpy concentrate is obtained which is particularly wellsuited for administration to pets and domestic animals.

EXAMPLE ll An anthelmintic 10 percent feed concentrate mixture of thefollowing constitution was produced:

10 parts of N-(3-trifluoromethyl-4-chlorophenyl)-S-(4'- chlorophenyl)dithiocarbamate, were added to 90 parts of a feed containing:

4-5 parts of roughage,

20 parts of crude protein,

64-65 parts of total nutrients,

8-1 1 pans of vitamins and quartz sand.

This mixture was mixed with standard chicken feed and was fed to hensinfested with Ascaridae. The concentration of active substance in thefeed was 0.25-0.5 percent. in the days following this treatment, greatelimination of Ascaridae by the hens was determined. There were no moreAscaridae or eggs thereof in the faces in the following 6 weeks.

EXAMPLE III A 50 percent powder of the following composition: 50 partsof N-(3,5-ditrifluoromethylphenyl)-O-(3'- trifluoromethylphenyl)thiocarbamate 2 parts of tylose/kaolin mixture 1:]

0.8 parts of sodium benzoate 0.05 parts of sodium lauryl sulfate partsof sorbitol monostearate 42.15 parts of white flour, is produced byintimately mixing the individual components. This powder is mixed withpulpy or dry feed concentrate and is fed for 3 days to pigs infestedwith nematodes. After feeding the pigs for l4 days normally with usualfeed concentrate, the pigs are again so fed. After this secondtreatment, the animals are free of worms to all intents and purposes.

EXAMPLE IV Parts of N-(3,S-ditrifluoromethylphenyl)-O-(3-trifluoromethylphenyl) thiocarbamate are intimately mixed with 90 partsof a nutritionally well balanced nutrient feed to form an additive toanimal feeds. The nutrient feed consists of:

roughage 4.5percent crude protein 18.5percent digestible proteinl5.7percent total nutrients 66.5percent vitamin A 9000 i.U/kg. vitaminD, I200 i.U/kg. vitamin B, 6 mgJkg.

The feed additive can be fed to pigs and sheep as such in a measuredquantity or, as a 0.03-0.001 percent mixture (calculated on the activesubstance), it can be admixed with the usual feed. The higher dosage canbe given for a short time or the lower dosage over a longer period. Thegeneral condition of the animals is improved and, with this, betterincrease in BEEF ta ns? EXAMPLE V wherein each of R and R independentlyfrom the other represents hydrogen, halogen or halogenoalkyl,

R represents hydrogen, halogen, nitro, hydroxyl, amino, carboxyl,carbamoyl, sulfamoyl, phenoxy, sulpho, alkyl, alkenyl, halogenoalkyl,alkoxy, alkylthio, alkoxyalkyl, al kylthioalkyl, alkylsulphinyl,alkylsulphonyl, S-alkylsulphonylamino, N-alkylsulphamoyl, N,N-dialkylsulphamoyl, N-alkylcarbamoyl, N, N-dialkylcarbamoyl,alkylamino, dialkylamino, acylamino, or alkoxycarbonyl,

R represents hydrogen, halogen or alkyl, and a salt, acceptable forveterinary purposes, of a compound of Formula l in which R is amino,with an acid, and a salt, acceptable for veterinary purposes of Formulain which R is carboxyl, with a base.

2. A compound as defined in claim 1, which is ofthe formu- 3. A compoundas defined in claim 1, which is of the formu- 4 V 7 or,

5. A compound as defined in claim 1, which is of the formula O1 la 8. Acompound as defined m claim 1, whlch 15 of the formu- 7 Fa u 6. Acompound as defined in claim 1, which is of the formu- 5 NHCS0 NHCOCH:la U V,

ClNH-CSOB1' 7 7 Br n 10 la9. A compound as defined m clalm l, whlch s ofthe formu- 7. A compound as defined in claim 1, which is of the formu- 7Cl 13 V n l NHCOS C F3 Cl UNITED STATES PATENT OFFICE CERTIFICATE OFCORRECTION Patent N D t d Septenlber 28 Inventor(s) Walter 'Iraber,Alfred Margot, Jean-Jacques Gallay It is certified that error appears inthe above-identified patent and that said Letters Patent are herebycorrected as shown below:

Col. 10 line 41: "sulfamoyl should read sulphamoyl Col. 10, line 46:after "alkyl" and before "and" there should appear one of X and Yrepresents sulfur and the other represents oxygen or sulfur Col. 12,line 5: the structural formula should appear as follows:

Cl NH-CS-O NHCOCH Signed and sealed this 2nd day of May 1972.

(SEAL) Attest:

EDWARD I-I.FLETCI-IER,J'R. ROBERT GOTTSCHALK Attesting OfficerCommissioner of Patents USCOMM-DC 60376-P69 w us, GOVSRNMINT PRINTINGornc: x90 o-aca-ssl

2. A compound as defined in claim 1, which is of the formula
 3. Acompound as defined in claim 1, which is of the formula
 4. A compound asdefined in claim 1, which is of the formula
 5. A compound as defined inclaim 1, which is of the formula
 6. A compound as defined in claim 1,which is of the formula
 7. A compound as defined in claim 1, which is ofthe formula
 8. A compound as defined in claim 1, which is of the formula9. A compound as defined in claim 1, which is of the formula